The Genetics of Hereditary Angioedema: A Review

Abstract

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

“…Inf). Genes in Group IV included those coding for two core proteins ( GPC2 90-92 and GPC5 93-95 ), three NDSTs ( NDST2 96-98 , NDST3 99-101 , and NDST4 102,103 ), two HS6STs ( HS6ST2 104,105 , HS6ST3 106,107 ), all HS3STs ( HS3ST1 108-110 , HS3ST2 111,112 , HS3ST3A1 113-115 , HS3ST3B1 115 , HS3ST4 116 , HS3ST5 117 , and HS3ST6 118,119 ), and one HS levels regulating genes (EXTL1 120 ). Based in current available data and literature records, it appeared that, at least in the absence of instigating stimuli, these genes are non-causative of disease and are not essential for normal development and homeostasis (Supp.…”

“…In peripheral tissues, several polymorphisms have been associated, along or in combination with other genes, with altered conditions or susceptibility to disease (Table 4). For instance in coronary artery diseases ( HS3ST1 ), ulcerative and Crohn’s colitis ( HS3ST2 ) 111 , chronic obstructive pulmonary disease ( HS3ST2 ) 112 , and hereditary angioedema ( HS3ST6 ) 119 . The importance of these genes in the regulation of response to stimuli is also supported by available knockout mice and biomedical research.…”

Hereditary angio-oedema with C1 inhibitor deficiency type I, an unusual stroke mimic

“…More than 700 causal variants in Serine Protease Inhibitor Gene 1 on chromosome 11 have been identified. This gene encodes for C1-INH, which is involved in the regulation of complement pathway, coagulation cascade and fibrinolytic system 2 3. Deficiency of C1-INH leads to increased serum levels of bradykinin, which acts as a potent inflammatory mediator by binding B2 and B1 receptors on vascular endothelial cells and it induces vasodilation and tissue oedematisation; both processes are responsible for acute C1-INH-HAE attack 8 9…”

“…A new type of hereditary angio-oedema, classified as hereditary angio-oedema with normal C1-INH (nC1-INH-HAE), has been described as having a similar clinical picture to C1-INH-HAE, but with normal plasma levels and activity of C1-INH. Currently, mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII, plasminogen, angiopoietin 1, kininogen 1, myoferlin and heparan sulfate glucosamine 3-O-sulfotransferase 6 3…”

Human Immune System Diseasome Networks and Female Oviductal Microenvironment: New Horizons to be Discovered

“…C1-INH regulates the activation of the classical and lectin complement pathways, coagulation and fibrinolysis cascades (López-Lera et al, 2014). Mutations in the SERPING1 gene are responsible for the largest cases of hereditary angioedema (HAE) (OMIM#106100), a rare autosomal dominant disorder that causes recurrent attacks of cutaneous angioedema, severe abdominal pain, and airway compromise (Santacroce et al, 2021). The disease course during pregnancy is unpredictable, with one study showing that seven Australian patients with HAE had reduced or absent attacks in the last two trimesters of pregnancy, while in the post-partum period they suffered from increased frequency and more severe attacks (Chinniah and Katelaris, 2009).…”